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Antiplatelet and antithrombotic effects of platelet glycoprotein iib iiia gpiib iiia inhibition by arginine glycine aspartic acid serine rgds and arginine glycine aspartic acid rgd o me y sc 46749

Antiplatelet and antithrombotic effects of platelet glycoprotein iib iiia gpiib iiia inhibition by arginine glycine aspartic acid serine rgds and arginine glycine aspartic acid rgd o me y sc 46749

Journal of Pharmacology & Experimental Therapeutics 256(3): 876-882

Arginine-glycine-aspartic acid (RGD) is the minimal sequence in fibrinogen that leads to recognition and binding to the glycoprotein IIb/IIIa platelet receptor during aggregation. Analogs of tetrapeptides containing the RGD sequence have been previously shown to block fibrinogen binding to activated platelets in vitro. SC-46749 is an analog of arginine-glycine-aspartic acid-phenylalanine in which the phenylalanine is replaced by O-methyltyrosine. In this study the biological activities of SC-46749 were examined and its actions compared with the tetrapeptide arginine-glycine-aspartic acid-serine (RGDS), one of the natural sequences on the fibrinogen .alpha. chain that binds to platelets. In vitro, SC-46749 was more potent that RGDS in inhibiting fibrinogen binding (IC50: SC-46749, 27 .mu.M; RGDS, 47 .mu.M), in preventing ADP-induced aggregation in human platelet-rich plasma (IC50 SC-46749, 32 .mu.M; RGDS, 95 .mu.M) and in inhibiting thrombin-induced aggregation in washed human platelets (IC50: SC-46749, 23 .mu.M; RGDS, 64 .mu.M). In rats, SC-46749 prevented collagen-induced thrombocytopenia with an ED50 of 0.87 mg/kg whereas RGDS did not inhibit the response by 50% at doses up to 10 mg/kg. SC-46749 inhibited thrombus formation in an electrically damaged rat carotid artery in a dose-dependent fashion whereas the effects of RGDS were biphasic. RGDS appeared to delay thrombus formation at lower doses but had no effect at higher doses. When infused in dogs for 15 min, SC-46749 prevented ex vivo collagen-induced aggregation at 4 mg/kg/min. These data demonstrate that SC-46749 is a potent inhibitor of platelet aggregation and platelet-dependent thrombus formation.

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Accession: 007028807

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PMID: 2005585

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